Low-dose folic acid could reduce homocysteine levels

Folic acid is known to lower plasma homocysteine levels, and high levels of the amino acid, hyperhomocysteinemia, are a marker for heart disease and thought to be a risk factor for atherosclerotic disease, which contributes to heart attacks.

The findings may also have an impact on cognitive function with epidemiological studies reporting that high levels of homocysteine associated with suspected or confirmed dementia. Indeed, the Framingham study reported that people with homocysteine levels above 14 micromoles per litre of serum had twice the risk of dementia.

This has led to the hypothesis that by lowering circulating levels of homocysteine by B vitamin supplements, the risk and occurrence of dementia could be reduced.

The new study, published in the journal Nutrition Research​ (Vol. 26, pp. 460-466), reports that even a low-dose folic acid supplement (400 micrograms) could lead to significant reductions in hyperhomocysteinemic elderly people.

Lead researcher Ping-Ting Lin from the Chung Shan Medical University, Taiwan, and co-workers recruited 46 people (42 men, average age 73) and randomly assigned to either a placebo group or a folic acid group (General Nutrition Corp.) for eight weeks. Compliance was ensured by 24-hour diet recalls at week 0 and week 8.

The researchers report that, while the low-dose folic acid supplements had no significant effect on homocysteine concentrations in the general study population, levels did significantly decrease in hyperhomocysteinemic subjects by 1.8 micromoles per litre.

"The significant result of this study was that a low dose of folic acid supplementation (400 microg/d) could significantly decrease plasma homocysteine concentration in hyperhomocysteinemic patients with CAD but not in normohomocysteinemia patients,"​ wrote the researchers.

Analysis of specific genotypes also showed a significant effect. The researchers looked at potential genetic defects in the metabolic pathway of homocysteine involving the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene mutation. People with the so-called TT homozygote genotype with low folate status are reported to have higher homocysteine concentrations than the other genotypes, putting this subset at increased risk of CAD and cognitive decline.

Low-dose folic acid supplementation for eight weeks for the TT genotype people led to a significant 2.1 micromoles per litre reduction in homocysteine levels, and 1.4 micromoles per litre for people who carry the T-allele either hetero- or homozygously.

The study does have several limitations, most notably the small number of participants and the short supplementation period. Nevertheless, the researchers concluded: "A low-dose (400 microg/d) rather than a high-dose of folic acid supplementation may be sufficient to reduce plasma homocysteine concentration in hyperhomocysteinemic patients with CAD."​

"However, folic acid supplements do not seem to lower plasma homocysteine in patients with CAD with normal plasma homocysteine level. Risk factors other than homocysteine level in these normohomocysteinemic patients with CAD need to be investigated further,"​ they said.

The link is being further examined by the B-Vitamin Treatment Trialists' Collaboration​ which should soon be better able to address the link between B-vitamins, homocysteine levels, cardiovascular health, and cognitive function.

Data should soon be available on three to seven years of supplementation with B vitamins on cognitive function on about 20,000 of the 50,000 participants with previous cardiovascular or renal disease in the 12 large homocysteine-lowering trials for the prevention of cardiovascular events.

It has been reported that vitamin B12 is a more important determinant of high homocysteine levels in people over 70 than folate, and some experts have called for future studies to focus on dietary supplementation of 1000 micrograms of B12 in elderly people.